Photolytic cyclization of an amino-keto acylate

ABSTRACT

Disclosed herein are novel N-acyl-3-aryl-3-azetidinols useful as intermediates. A method is provided for their direct preparation from acyclic starting materials. These N-acyl-3-aryl-azetidinols provide a convenient route to the 3-azetidinol series.

United States Patent Gold Aug. 5, 1975 PHOTOLYTIC CYCLIZATION OF ANAMINO-KETO ACYLATE [56] References Cited [75] Inventor: Elijah H. Gold,West Orange. NJ. UNITED STATES PATENTS Assigneez schering corporaionKenilworth 3,711,464 H1973 Hensler et ul 20 4/l58 R J PrimaryExaminer-Howard S. Williams [22] Filed: Mar. 20, 1974 Arlorney. Agent,or Firm-Bruce M Eisen; Stephen B. 21 Appl. No.: 452,870

Related U.S. Application Data 57 ABSTRACT [60] Dwisio" 0f f- N MDisclosed herein are novel N-acyl-3-aryl-3-azetidinols ilbanifrezcswjhich lllgzgimglulzjofl-lllli-pflfl o useful as intermediates. A methodis provided for their une a direct preparation from acyclic startingmaterials. These Nacyl-3-aryl-azetidinols provide a convenient route tothe 3 azetidinol Series 58 Field of Search 204/158 R 1 Claim. N0Drawings PHOTOLYTIC CYCLIZATION OF AN AMINO-KETO ACYLATE This is adivision of application Ser. No. 237,931, filed Mar. 24, 1972, which inturn is a continuation-inpart of my copending application Ser. No.741,205, filed June 28, 1968, both now abandoned.

In recent years there has been much interest in the 3-azetidinol seriesof compounds. Heretofore the preparation of intermediates for thesecompounds has been a time-consuming and tedious chore and has usuallyinvolved chemical transformations of preformed azetidinols.

lt has now been found that N-acyl-3-phenyl-3- azetidinols can be easilyand rapidly synthesized from acyclic starting materials.

The invention sought to be patented in its process aspect comprises thephotolysis of an amino-keto acylate to yield the correspondingN-acyl-3-aryl-3-acetidinol.

This invention relates to compositions of matter having the molecularstructure of azetidine in which the ring nitrogen atom is acylated andin which the 3- carbon atom in the ring is substituted by both a phenylgroup and a OR,-; group. These chemical compounds may optionally have alower alkyl radical substituted in each of the 2 and 4 carbon atompositions in the azetidine ring and may also optionally havesubstituents on the phenyl nucleus. These compounds may be used asintermediates for preparing such compounds asNalkyl-3-aryl-3-azetidinols which have utility per se as analgesics.

More specifically, the compounds of this invention may be represented bythe structural formula:

wherein R, and R are each hydrogen or lower alkyl; R is hydrogen, loweralkyl or a lower alkanoyl radical; X is hydrogen, fluorine, chlorine,bromine, lower alkyl, hydroxy, lower alkoxy or trifluoromethyl; and Z isacyl.

The lower alkyl radicals referred to above (including the alkyl portionof the lower alkoxy and lower alkanoyl radicals) may be straight orbranched-chain cyclic and may include, for example, methyl, ethyl,npropyl, iso-propyl, n-butyl, sec-butyl, iso-amyl, n-hexyl, cyclopropyl,cyclopentyl, cyclohexyl and the like. Exempliferred acyl radicalsinclude p-toluencsulfonyl, methylsulfonyl, benzoyl andperfluoroloweralkanoyl.

In those instances wherein the organic radical contains a phenyl moiety,said moiety may be substituted with such substituents as lower alkyl,trifluoromethyl, fluoro, chloro, bromo, hydroxy or lower alkoxy.

. The compounds of formula I wherein R is hydrogen can be prepared bythe photolytic cyclization of an amino-keto acylate of formula (II) byirradiation with light having a wavelength greater than 280 mu.

wherein R,, R X and Z are as above defined.

The cyclization is carried out under a nitrogen atmosphere in a suitablesolvent such as ether, or an alcohol, e.g. butanol and ethanol.

The reaction mixture is photolyzed until the aminoketo acylate isconsumed. The resulting mixture is filtered and the crude product isgenerally isolated from the filtrate by such standard techniques aschromatography or crystallization. The crude product may then bepurified according to standard techniques, e.g. fractionalcrystallization.

In an alternate manner, the compounds of formula I may also be preparedby condensing an N-acyl-3- azetidinone (III) with a phenyl-metalcompound (1V) such as phenylmagnesium bromide. Compounds of formula lllmay be prepared by the oxidation of a corresponding 3-azetidinol.

wherein R,, R X and Z are previously defined and m is a reactive metalhalide such as lithium or magnesium bromide.

The reaction is usually carried out at low temperatures (e.g. 10 to SOC)in a suitable organic solvent such as ether. The phenyl metal halide isusually added to the ketone in solution in a dropwise manner. Thereaction is allowed to go to completion, a process usually requiringless than one hour and the reaction'mixture is decomposed with a basicreagent such as lll /r aqueous ammonium chloride. The resulting3-acyl-3-aryl-3- azetidinol is then isolated and purified according tostandard techniques.

in those instances wherein it is desired to have an R substituent otherthan hydrogen. it may be introduced into theN-aeyl-3-phenyl-3-azetidinol molecule according to standard techniquesshown to the art for esterifying or ethcrifying a hydroxyl group.

The following examples are illustrative of the preparation ofrepresentative compounds of this invention.

EXAMPLE 1 Preparation of N-bcnzoyl-3-phenyl-3-azetidinol A. Preparationof N-benzoyl-3-azetidinone To a stirred mixture of 2.5 g. ofN-benzoyl-B- azetidinol. 2i g. of triethylamine in 35 ml. of DMSO. addrapidly. in a dropwise manner. a suspension of 7.0 g. of pyridine sulfurtrioxide in 35 ml. of DMSO and stir for [5 minutes. Remove most of theDMSO in vacuo at 60C and chromatograph the residue on l()() g. of silicagel. Elute with chlorform and collect 2.4 g. of the crude compound ofthis example from the front running yellow band. Recrystallize fromisopropyl ether.

B. Preparation of N-benzoyl-3-phenyl-3-azetidinol To a stirred solutionof L8 gm. of N-benzoyl-3- azetidinone dissolved in ml. of ether at C.slowly add. in a dropwise manner. ll ml. of ().l N- phenylmagnesiumbromide in ether. Stir for ten minutes and then decompose with 15 ml. of[072 aqueous ammonium chloride. Remove the ether phase and extract theaqueous phase twice with 40 ml. portions of ether. Dry the combinedether extracts over sodium sulfate. Filter and remove the ether in vacuoto obtain 2.0 g. of N-benzoyl-3-phcnyl-3-azetidinol. By substitutingequivalent quantities of: N-benzoyLZ-methyl-3-azetidinone.N-mesyl-2.4-dimethyl-3-azetidinone. N-tosyl-3-azetidinone,N-carbobenzyloxy-3-azetidinone. N- y.y.y-trifluoropropionyl]2.4-diisopropyl-3- azetidinone. or N-bcnzoyl-2-ethyl-3-azetidinonc inplace of the N-benzoyl-3-a2etidinone. and by following substantially thesame reaction procedure of this example. there is producedN-benzoyl-Z-methyl-S- phenyl-3-azetidinol.

N-mesyl-2.4-dimethyl-3-phenyl-3-azetidinol.N-tosyl-3-phenyl-3-azetidinol. N-carbobenzyloxy-3-phenyl-3 azetidinol.N-[ y.-y.y trifluoropropionyl ]2.4-diisopropyl-3- phcnylG-azctidinol,and N-benzoyl-Z-ethyl-3-phenyl-3-azetidinol.

tivcly. Similarly by substituting equivalent quantities of:p-chlorophcnylmagnesium bromide. p-trifluoromethylmagnesium bromide.o-fluorophenylmagncsium bromide. p-methoxyphenylmagnesium bromide. orm-ethylphenylmagnesium bromide in place of the phenylmagnesium bromide.and by following substantially the same procedure of this example. thereis produced:

N-benzoyl-3( p-chlorophenyl l-3 azetidinol. N-benzoyl3-(ptrifluoromethylphenyl )-3-azetidinol. N-benzoyl-3-( o-fluorophenyl)-3-azctidinol. N-benzoy'l-3-( p-methoxyphcnyl )-3-azetidinol. andN-benzoyl-3-( m-cthylpheny] )-3-azetidinol.

respec- EXAMPLE 2 Preparation of N-(p-tolucnesulphonyl-2-methyl-3-phcnyl-3-azetidinol In a nitrogenatmosphere. using a Hanovia 450 watt medium pressure ultraviolet lamp ina water cooled pyrcx immersion well. internally irradiate 23.3 g. of N-ethyl-N-a-p-toluenesulphonamidoacetophenone dissolved in 4 liters ofether. with stirring for six hours. Filter. remove the ether in vacuo.crystallize the residue from I00 ml. of carbon tetrachloride and obtain15.0 g. of the product of this example.

EXAMPLE 3 Preparation of N-henzoyl-Ii-phenyl-Ii-azetidinol In a nitrogenatmosphere. using a Hanovia 450 watt medium pressure ultraviolet lamp ina water cooled pyrex immersion well. internally irradiate 16 g. of N-methyl-a-benzamidoacetophenone [J. Am. Chem. Soc., 78. 1941 (1956)]dissolved in 2.3 liters of ether. with stirring for IS hours. Filter thesolution and chromatograph the crude product. after removing most of thesolvent on 900 g. of silica gel. Wash the column with about 6 liters ofchloroform and then elute the desired product with 371 methanol inchloroform (containing 0.7571 ethanol) and obtain 9.4 g. of solidbenzoyl-3-phenyl-3-azetidinol.

Using the above-described methods and employing analogous reagents. onecan similarly prepare the other compounds of this invention. Forexample. using an R,. R mono or dialkyl-substituted amino-ketoacylate.one can prepare the corresponding l-acyl-Z-alkyl or 2.4-dialkyl-3-phenyl-3-azctidinols. For example. by substituting for the Nmethyl-a-benzamidoacetophenone reactant of the above example:

N-( l-isobutyl )-N-oz-ptoluenesulfonamidoacctophcnonc.

a-[ N-ethyl-N-p-toluenesulfonamido1- propiophenone. or

N-propyl-N-a-toluenesulfonamidoacetophenone. one may obtain:

N-tosyl-Z-isopropyl-3-phenyl-3-azctidinol.

Ntosyl-2.4-dimethyl-3-phenyl-3-azetidinol. and

N-tosyl-3-ethyl-3-phenyl-3-azetidinol. respectively.

EXAMPLE 4 Preparation of N-trifluoromethylacetyl-3-phenyl-3-azctidinolA. Preparation of N-methyl-N-trifluoroacetyl-aaminoacetophenone Add 23.1g. of trifluoroaceticanhydride to 14.9 g. ofN-methyl-a-acetaminoacetophenone in 65 ml. of dichloromethane. Refluxthe mixture for one hour. Wash the solution with saturated sodiumbicarbonate and then with water. Dry over magnesium sulfate. filter andremove the solvent in vacuo and obtain the product of this step.

8. Preparation of N-trifluoromethylacetyl-3-phenyl- 3azetidinol in anitrogen atmosphere using a Hanovia 450 watt medium pressure ultravioletlamp in a water cooled pyrex immersion well, internally irradiate l.()g. of N- methyl-N-trifluoroacetyl-a-aminoacctophenone dissolved in 250ml. of ether. with stirring for one hour. Filter and isolate the productof this example.

Similarly by replacing the N-methyl-N-trifluoroacetyl-oz-aminoacetophenone reactant with equivalent quantities ofN-methyl-N-pentafluoroethylacetyl-aaminoacetophenone;N-methyl-N-difluoromcthylacetyl-a-aminoaeetophenone; andN-methyl-N-propionyla-aminoacetophenone. and following substantially thesame procedure of this example there is produced the correspondingl-acylated-3-phenyl-3-azetidinol.

EXAMPLE 5 Preparation of N-carbobenzyloxy-2-methyl-3-phenyl-3-azetidinolA. Preparation of N-carbobenzyloxy-N-ethyl-aaminoacetophenone Add. in adropwise manner, 20.4 g. of earbobenzyloxy chloride to a stirredice-cooled mixture of 16.3 g. of N-ethyl-a-aminoacetophenonehydrochloride and l2.7 g. of sodium carbonate in [25 ml. of water andmaintain the reaction temperature at about 25C. When the addition iscomplete, stir for one hour at room temperature and extract the productwith ether. Wash the ether extract successively with 5% hydrochloricacid. water saturated aqueous sodium bicarbonate and finally with water.Dry over magnesium sulfate and filter. Remove the ether in vacuo andobtain the product of this step.

B. Preparation of N-carbobenzyloxy-2-methyl-3- phenyl-3-azetidinol In anitrogen atmosphere using a 450 watt Hanovia medium pressure ultravioletlamp in a water-cooled pyrex immersion well, internally irradiatc l.5 g.of N- carbobenzyloxy-N-ethyl-a-aminoacetophenone dissolved in 250 ml. ofether. Stir for 1 hour. Filter. and isolate the product of this example.

EXAMPLE 6 Preparation of N-methanesulfonyl3-phcnyl-3-azctidinol A.Preparation of N-methanesulfonyl-N-methyl-aaminoacetophenone To astirred. ice-cooled, mixture of l3.l g. of Z-(N- methylaminomethyl)-2-phenyl-l .3-dioxolane and 14.8 g. of sodium carbonate in I00 ml. ofdry acetonitrile. add 12. l g. of methanesulfonyl chloride in ml. of dryacetonitrile over a 10 minute period. Remove the cooling bath and stirfor two hours. Cool in an ice bath and add 140 ml. of 571 aqueous sodiumhydroxide. Separate the layers. wash the aqueous layer once withdichloromethane. combine the organic extracts and remove the solvent invacuo to give the compound of this step.

To this stirred residue. add 50 ml. of methanol and I0 m]. ofoN-hydrochloric acid and reflux for two hours. Cool and Filter off theproduct of this reaction.

B. Preparation of N-methanesulfonyl-3-phenyl-3- azetidinol Using aHanovia 450 watt medium pressure ultraviolet lamp. and under a nitrogenatmosphere, in a water cooled pyrex immersion well intemally irradiate1.5 g. of N-methanesulfonyl-N-methyl-0:- aminoacetophenone dissolved in250 ml. of ether. Irradiatc the mixture for 50 minutes. Filter andreduce the volume to about ll) ml. whereupon the desired compoundcrystallizes out. Recrystallize from a chloroform-hexane mixtureobtaining the compound of this example.

By substituting equivalent quantities of:

N-cyclopropylcarbonyI-N-methyl-uaminoacetophenone.

N-trifluoromethylsulfonyI-N-methyl-a-aminoacetophenone.

N-methoxycarbonyl-N-methyl-aaminoacetophenone.

N-tosyl-N-mcthyl-a-aminoacetophenone.

Nphenethylcarbonyl-N-methyl-aaminoacetophenone, and

N-benzylsulfonyl-N-methyl-a-aminoacetophenone.

for

the N-methanesulfonyl-N-methyl-aaminoacetophenone of the above example.and by following substantially the same procedure there is produced:

N-cyclopropylcarbonyl-3-phenyl-3-azetidinol.

N-trifluoromethylsulfonyl-3-phenyl-3-azetidinol.

N-methoxycarboxyl-3-phenyl-3-azetidinol.

N-tosyl-3-phenyl-3-azetidinol.

N-phenethylcarbonyl-El-phenyl-3-a2etidinol. and

N-benzylsulfonyl-3-phenyl-3-azetidinol. respectively.

Numerous variations of the above examples will be apparent to oneskilled in the art of chemistry. and as such are contemplated as beingwithin the scope of this invention.

The N-acyl-Ilphenyl-3 azetidinols of this invention may be deacylatedaccording to standard techniques such as hydrolysis. electrolysis. orreductive cleavage. In those instances wherein the acyl moiety is anaryl sulfonyl group electrolysis is the preferred deacylation technique.When the acyl moiety is a sulfonyl group. metal hydride reductivecleavage is preferred. after suitably protecting the alcohol moiety.

The free 3-aryl-3-azetidinols may be N-alkylated in a variety ofmanners. For example. it can be condensed at ambient temperatures withan appropriate oxoderivative of the desired N-alkyl moiety in an inertorganic solvent. such as ethanol. to yield the correspond ing iminccondensate. The latter can be reduced in situ. and may. for example. beconducted catalytically by hydrogenation over a palladium catalyst in asuitable solvent. Exemplifying the oxo-compound are formaldehyde.acetaldehyde. acetcyclohexylacetaldchyde. 4-methyleyclohexanone and thelike.

Other N-alkyl. or aralkyl derivatives may be produced directly byreduction of the suitable Z ra cals. For example. to directly produce aN-benzyl-3-pnenylazetidinol. the acyl group Z can be benzoyl and thedesired compound can be produced directly by standard reduction methods,e.g. lithium-aluminum hydride in tetrahydrofuran.

It is. of course. recognized that the compounds of this inventionembrace geometric isomers when either or both R and R are alkyl. Thecompounds of this invention also exhibit steroisomerism.

I claim:

I. A process for preparing a compound having the structural formula:

wherein R and R are each hydrogen or lower alkyl; X wherein R R X and Zare as previously defined, by is hydrogen fluorinc Chlorinebmminev lowerulkyl, means of irradiating said amino-keto acylate with light hydroxy,lower alkoxy or trifluoromethyl; and Z is acyl which comprises thephotolytic cyclization of an amino-keto acylate:

having a wavelength greater than 280 mp.

1. A PROCESS FOR PREPARING A COMPOUND HAVING THE STRUCTURAL FORMULA: